In the pharmaceutical industry much work has been devoted during recent years to improving the effectiveness, safety and practicality of orally administered drugs. This invention is specifically directed toward the goal of prolonging the release of an orally taken drug over a period of several hours. Such a prolonged release has the following advantages: peak blood levels of the drug, which sometimes represent toxic levels, are avoided since not all the drug is released into the stomach at the same time; secondly, drug concentrations in the blood are maintained for a longer time within the therapeutic range, thereby increasing the overall effectiveness of the drug and reducing the overall dose-size necessary for treatment; thirdly, drugs which would have to be taken in conventional form several times daily for the treatment of chronic diseases, can be administered in once- or twice-a-day dose forms, which are safer and more convenient for the patient.
Conventional dose forms of orally taken drugs are tablets or pills in which the drug is compounded with a water soluble gum or polysaccharide which quickly dissolves or disintegrates in the stomach. An extension of this technology are tablet coatings and multiple coatings around tablets which retard the disintegration and dissolution speed. Material and synthetic polymers with different molecular weight and water solubilities are used for this purpose. U.S. Pat. No. 3,432,592 describes an advanced formulation of this sort, which consists of injection-molded water soluble polymers, like poly(vinyl alcohol), containing drugs dispersed therein.
None of these methods work satisfactorily. Tablet disintegration is fast and poorly reproducible since it is to a large degree a function of physical motion in the stomach. Therefore, polymeric dosage-forms were developed in which the drug-release is diffusion-controlled, independent of physical variables other than polymer compositions and morphology. In these dosage forms the polymer is passed through the body without degradation.
Examples of such a monolithic dose form with uniform drug concentrations are described in Australian Pat. No. 16202, and in U.S. Pat. No. 3,390,050, wherein hydrophilic polymer beads are synthesized in the presence of a drug. U.S. Pat. No. 4,267,138 describes an oral dose form in which the release of an active ingredient is controlled by a coating surrounding drug containing particles, which are compressed into tablets. The coatings are complicated mixtures of plasticized synthetic polymers and water.
U.S. Pat. No. 3,538,214 also describes coated tablets, in which the coating acts as a porous membrane, letting water pass through to dissolve the enclosed drug, which in turn diffuses to the outside. Porous membranes are obtained and their porosity is controlled by addition of auxiliary, water-soluble substances to the coating material which are loaded out prior to drug-diffusion. Similar membrane enclosed oral dose forms are described in U.S. Pat. Nos. 3,854,480, 3,993,072 and 4,244,941.
When used in combination with water-soluble drugs, the above mentioned membrane devices all have the drawback of uncontrollable expansions and breaking due to osmotic pressure build up. This problem was overcome by applying the osmotic pump principle, as described in J. Pharm. Sci. 64, 1981 (1975). This consists of a semipermeable membrane, which lets only water diffuse into the tablet to dissolve the drug, which in turn is pumped out through a pinhole in the membrane. Although this method works well with moderately soluble drugs, it is less applicable to highly water-soluble ingredients because the osmotic pressure quickly become too high as the drug-reservoir is dissolved. As in all membrane devices, constant release is achieved only as long as an undissolved drug reservoir is present in the core. Another disadvantage of the osmotic pump is the high level drug concentration existing at the exit hole which can lead to irritation of the stomach wall.
The above mentioned monolithic polymer-drug compositions of U.S. Pat. No. 3,390,050 and Australian Pat. No. 16202 do not have these disadvantages. In U.S. Pat. No. 3,390,050 no final polymer purification can be carried out since the drug is incorporated during synthesis.
Australian Pat. No. 16202 describes the use of a water swellable poly(2-hydroxyethyl methacrylate) or copolymers of 2-hydroxyethyl methacrylate to imbibe drugs from an aqueous solution. The dried polymer-drug composite forms a controlled oral release device. A similar approach, but using water-swellable polymers (hydrogels) which are themselves two-phase polymers and which exhibit a much wider range of swelling in water and organic solvents is described in U.S. Pat Nos. 4,192,827 and 4,136,250. Although in all these polymers certain drugs can be imibibed in sufficient amounts to make the manufacture of practical dosage forms possible, their relatively high degree of swelling in water (30 to 80%) is concomitantly accompanied by a relatively low degree of swelling in organic solvents. Typically the ratio of % swelling in ethanol to % swelling in water for these hydrogels lies in the range of 1/1 to 2/1.
Furthermore, in these hydrogel drug-carriers, as a high degree of swelling in water is accompanied by a high degree of swelling in organic solvents, concomitantly a low degree of swelling in water is accompanied by a similarly low degree of swelling in organic liquids like ethanol. This limited swelling ability of the hydrogels limits the amount of drug which can be imbibed into them from a drug solution, be it aqueous or organic in nature. If the polymer swells to a larger degree in a suitable organic solvent than in water, then higher drug-loadings can be achieved by loading from, for instance, ethanol/drug solutions than from aqueous solutions provided the drug is soluble in ethanol. The use of organic solvents to imbibe hydrogels with a drug for later release has also been described in U.S. Pat. No. 4,192,827.